16alpha-fluoro-4-androsten-17alpha-ol-3-one and esters thereof



United States Patent 3,059,000 IGu-FLUORO-4-ANDROSTEN-17a-0L-3-ONE ANDESTERS THEREOF Edward J. Becker, Princeton, and Paul P. Lemanski,

Nixon, Nl, assignors to Olin Mathieson Chemical Corporation, New York,N.Y., a corporation 'of Virginia No Drawing. Filed Sept. 1, 1961, Ser.No. 135,469 4 Claims. (Cl. 260-3914) This invention relates to, and hasfor its object the provision of new steroids and more particularly tothe new steroids l6a-fluoro-4-androsten-l7a-ol-3-one and 17- estersthereof.

The new steroid of this invention, 16u-fluoro-4-androsten-17a-ol-3-oneis prepared by reducing 16u-fluoroandrostenedione by treatment withsodium borohydride, whereby a mixture of16u-fluoro-4-androsten-17a-ol-3-one and l6a-fluoro-testosterone areobtained and separating the mixture to yield pure16a-fluoro-4-androsten'1711-01-3- one. To prepare the esters of thisinvention, 16a-fluoro- 4-androsten-17a-ol-3-one, either alone or inmixture with l6m-fluorotestosterone, is reacted with the desiredacylating agent. If a mixture is used, the resulting mixture can then beseparated chromatographically to yield the desired ester of16a-flllOI0-4-aI1dI'OSt6I1-17ct-O1-3-O116.

Although any acylating agent may be used, the preferred compounds arethe acyl halides and acid anhydrides of hydrocarbon carboxylic acids ofless than ten carbon atoms, such as the acyl chlorides and acidanhydrides of lower alkanoic acids (e.g., acetic, propionic, butyric,enanthic and hexanoic acid), lower alkenoic acids, cycloalkanecarboxylicacids, cycloalkenecarboxylic acids, monocyclic aromatic carboxylic acids(e.g., benzoic and p-toluic acid), and monocyclic aralkanoic acids(e.g., phenacetic, fl-ph'enylpropionic and B-phenylbutyric acid). Theacylating reaction is preferably conducted in the presence of a base,such as pyridine.

16 fluoro 4 androsten 17cc o1 .3 one (and its esters), unlike theepimeric l6oz-fluorotestosterone, is devoid of androgenic activity andpossesses myotrophic activity. Hence, the compounds of this invention,unlike their epimers, can be used to decrease the required dose ofandrogenic steroids, such as testosterone, in the treatment of proteindepletion states, being formulated for such administration in the sametype of preparations as 17a-ethy1-19-nortestosterone, for example, withconcentration and/ or dosage based on the activity of the particularcompound.

The following examples illustrate the invention (all temperatures beingin centigrade):

EXAMPLE 1 16a-Flu0r0-4-Andr0sten-1 7 a-0l-3-0ne 177.6 g. ofl6a-fluoroandrostenedione is dissolved in 7.88 1. of methanol and cooledto 3. During 15 minutes, 8.417 g. of sodium borohydride is added and thesolution is maintained at for one and one-quarter hours. Ice is thenadded to the solution, followed by 490 ml. of 1 N HCl. After one hour,the solution and crystals are poured into 24 1. of ice water. Theproduct is filtered and dried overnight in vacuum to give about 134 g.of a mixture of 16a-fluoro-4-androsten-17a-ol-3-one andl6a-fluorotestosterone. 132 g. of this mixture is dissolved in 863 ml.of anhydrous pyridine and 278 ml. of propionic anhydride is then added,While swirling the solution. After 17 hours at room temperature thesolution is diluted with ice and 4000 ml. of 10% sulfuric acid. Theproduct is isolated by chloroform extraction (3 x 1.4 1.). After washingand drying, the organic phase is evaporated to a crystalline residue,weighing about 168 g. Recrystallization from acetone/hexane gives about57.5 g., M.P. about ZOO-209 and a second crop of 6.3 g. Both crops arecombined and recrystallized from acetone/water to give about 58.1 g. ofl6a-flu0r0testosterone propionate. :Paper chromatography demonstratesthat the motor liquor contains two substances. This mother liquor ischromatographed on alumina. No crystalline material is obtained butbenzene/hexane 50:1, benzene and benzene/chloroform 25:1, 25:3, 25:6 and3; 1 provides a uniform substance, as indicated by paper chromatography.A sample of these fractions (971 mg.) is saponified in aqueous sodiumcarbonate. After extraction into chloroform and treatment with waterfollowed by sodium sulfate the solution is evaporated to a crystallinemass. Recrystallization from acetone/hexane gives about 485 mg. ofl6a-fluoro-4-androstene-l7a-ol-3-one, M.P. about 183-185. \A secondrecrystallization brings the melting point to about 185-l88, [c1 +50",18.56 mg./2 ml. chloroform.

EXAMPLE 2 16u-Flu0r0-4-Andr0sten-1 7a-Ol-3-0ne Acetate 132 mg. ofl6u-fluoro-4-androsten-17a-ol-3-one is dissolved in 3 ml. of anhydrouspyridine and 3 of acetic anhydride is then added, While swirling thesolution. After 18 hours at room temperature, the solution is dilutedwith ice and 15 ml. of 10% sulfuric acid. The product is isolated bychloroform extraction and evaporation of the chloroform.

Similarly, by substituting other acylat-ing agents for the aceticanhydride in the procedure of Example 2, the corresponding esters of16a-fluoro-4-androsten-17a-ol-3-one are obtained.

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

l. A compound selected from the group consisting of16u-fluoro-4-androsten-l7a-ol-3-one and esters thereof with hydrocarboncarboxylic acids of less than ten carbon atoms.

2. 16u-fluoro-4-androsten-17a-ol-3-one.

4. 16m-fluoro-4-androsten-17a-ol-3-one propionate.

References Cited in the file of this patent UNITED STATES PATENTS2,857,403 Fried et al, Oct. 21, 1958

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 16A-FLUORO-4-ANDROSTEN-17A-OL-O-ONE AND ESTERS THEREOF WITH HYDROCARBON CARBOXYLIC ACIDS OF LESS THAN TEN CARBON ATOMS. 